The heart works without resting, requiring enormous amounts of energy to continuously pump blood throughout the body. Because of its considerable energy requirements, the heart is vulnerable to oxidative stress caused by the generation of endogenous reactive oxygen species (ROS). Therefore, the heart has effective regulatory and adaptive mechanisms to protect against oxidative stress. Inherited or acquired mitochondrial respiratory chain dysfunction disrupts energy metabolism and causes excessive ROS production and oxidative stress. The physiological cardiac response to oxidative stress can strengthen the heart, but pathological cardiac responses or altered regulatory mechanisms can cause heart disease. Therefore, mitochondria-targeted antioxidants have been tested and some are used clinically. In this review, we briefly discuss the role of mitochondrial DNA mutations, mitochondrial dysfunction, and ROS generation in the development of heart disease and recent developments in mitochondria-targeted antioxidants for the treatment of heart disease.